Membrane proteins function as mediators for exchange of material and information across cell membranes as well as converters of electro-osmotic, mechanical, and chemical energy in cells. These proteins are the targets of most pharmacological interventions and their function is related to many diseases. Often the function of a membrane protein is coupled to the membrane environment through mechanical or electrostatic forces. Advances in biomolecular modeling using large parallel computers permit now the in situ simulation of membrane proteins, the latter requiring, however, simulation volumes of more than 100, 000 atoms. As developers of the respective computational tools, we seek to utilize them in a systematic research program investigating the physical mechanisms by which membrane channels control transmembrane traffic of a wide range of compounds and the maintenance of membrane potentials. Research will focus initially on (1) protein of the aquaporin family, water and glycerol channels for which models of several medically relevant proteins will be constructed and investigated; the proteins are linked to diseases like diabetes insipidus, cataracts, and Sjorgen's syndrome; (2) the mechanosensitive channel MscL for which mechanical gating mediated through stretched and deformed lipid bilayers will be studied; the proteins are linked to diseases like hypertension and cardiac arrhythmia; (3) the chloride channel CIC for which we seek to identify mechanisms of ion conduction and gating; the protein is linked to inherited diseases that affect the muscles, notably, some forms of myotonia, as well as the kidneys, such as Dent's disease and Bartter's syndrome. The proposed research seeks a description of the three types of membrane channels at a level of unprecedented detail and without sacrificing native environment and exact physical interactions. [unreadable] [unreadable]